I. Field of the Invention
The present invention relates generally to the field of cell biology, cell physiology, medicine, and oncology. More particularly, it concerns methods for regulating osteoclastogenesis in a subject in need thereof, and particularly osteoclastogenesis related to cancer-induced bone destruction.
II. Description of Related Art
Breast cancer is the most common female malignancy in the U.S. and is the second leading cause of cancer death in women. Women with breast cancer are at risk for bone metastases. 5 to 10% of patients with breast cancer will initially present with metastatic disease to the bone. Patients with osteolytic bone disease from metastatic breast cancer are at increased risk for pathologic fractures, bone pain, cord compression and hypercalcemia. The current standard of care for treating bone metastases is bisphosphonate therapy, which delays skeletal events, but does not completely prevent them. In addition, not all patients respond to this treatment. While a more effective treatment is desired, a further biological and molecular dissection of this disease is required. Receptor activator of NF-κB (RANK) and its ligand (RANKL, also known as TRANCE/ODF/OPGL) are essential mediators of osteoclastogenesis and have been implicated in various diseases, which include rheumatoid arthritis, osteoporosis, giant cell tumor of bone, Paget's disease, metastatic breast and prostate cancer, multiple myeloma, and familial expansible osteolysis. Osteoprotegerin (OPG, also known as OCIF/TR1) is a soluble, decoy receptor that inhibits RANKL from binding to its cell surface receptor RANK.
Knockout mouse models of RANKL, RANK, and OPG have demonstrated an essential role of these molecules in osteoclastogenesis (i.e., bone remodeling). The biological importance of these molecules is underscored by the induction of severe osteoporosis by targeted disruption of OPG and by the induction of osteopetrosis by targeted disruption of RANKL or by over expression of OPG. Thus, osteoclast formation may be attributed to the relative ratio of RANKL to OPG in the microenvironment of bone marrow, and alterations in this balance may be a major cause of bone loss in many metabolic bone disorders. Similar to RANKL -/- mice, targeted disruption of RANK also leads to an osteopetrotic phenotype. Both RANK -/- and RANKL -/- mice exhibited absence of osteoclasts, indicating the essential requirement of these molecules for osteoclastogenesis. Furthermore, RANK and RANKL are required for lymph node organogenesis and early B and T cell development. Additionally, mice lacking TRAF6, c-Src, c-Fos, or the NF-κB subunits p50/p52 also display an osteopetrotic phenotype; though these mutant mice have osteoclasts, these cells apparently have defects in bone desorption. Thus, RANKL and RANK as well as their cytoplasmic signaling molecules are the governing factors that regulate normal bone homeostasis.
The relationship between the importance of RANK/RANKL/OPG in bone remodeling and that most cancer-induced bone destruction is due to increased osteoclastic activity suggests a major role of RANK/RANKL/OPG in bone diseases and cancer. Besides the involvement of RANK/RANKL/OPG in osteoporosis, recent reports suggest a potential role of these molecules in other diseases including rheumatoid arthritis, giant cell tumor of bone, Paget's disease, and familial expansible osteolysis (due to a mutation in axon 1 of RANK). Metastatic breast and prostate cancers have the ability to invade and grow as metastases in bone causing osteolytic lesions. In metastatic tumor mouse models, in which the tumor causes increased osteoclastogenesis and bone destruction, systemic administration of OPG reduces tumor-mediated bone destruction and pain associated with bone cancer. Thus, targeting the RANK signal transduction machinery could potentially be used as a therapeutic strategy to inhibit unwanted bone destruction associated with cancer and metabolic bone disorders. Additional strategies to prevent unwanted bone destruction associated with metastatic cancers, or conditions associate with or related to bone loss are needed.